New Chemical Scaffolds to Selectively Target the Trypanothione Metabolism
Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay in Medicinal Chemistry of Neglected and Tropical Diseases, 2019
In addition to antimonials, several metals, such as As(III), gold(I) and silver derivatives, are effective against Leishmania (Colotti et al. 2018). One of the target of these metals is the trypanothione reductase. Baiocco and coworkers have shown that As2O3 is able to inhibit TR of L. infantum in the micromolar range but with an inhibition constant one order of magnitude higher that antimonials (Ki = 14 ± 4 μM) (Baiocco et al. 2009a). The ability to bind the cysteines makes gold compounds able to inhibit TR with high efficiency. Auranofin (12, Table 3), used for decades against rheumatoid arthritis (Colotti et al. 2018), is also able to inhibit L. infantum TR. Indeed, auranofin is able to inactivate the enzyme with high efficiency (Ki = 0.15 ± 0.04 μM), thereby killing the parasite in the promastigote stage (IC50 = 9.7 ± 1.0 μM). The low-resolution crystal structure of auranofin–TR complex allowed the comprehension of the molecular basis of this inhibition (Ilari et al. 2012). As expected, the gold ion was found to be tightly bound to the two catalytic cysteines (Cys52 and Cys57) in the active site of the enzyme, thereby hampering hydride transfer from the protein to trypanothione, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin inhibits TR through a dual mechanism (Figure 4B and 4C).
Entamoeba histolytica
Dongyou Liu in Laboratory Models for Foodborne Infections, 2017
A comparative study of experimental cecal amoebiasis to evaluate amoebicides in the mouse, hamster, and rat was developed in India. The authors found different responses for each animal and proposed the mouse model as the most useful for the primary screening of antiamoebic compounds [97,98]. In another study, the cytotoxic effect of amide derivatives of trifluoromethionine (TFM) against E. histolytica was evaluated. Amoebae but not mammals possess l-methionine γ-lyase, an enzyme that hydrolyzes TFM and its derivatives, which makes it a good target for amoebicidal activity [99]. Interestingly, a high-throughput screening for compounds effective against amoeba identified auranofin, an FDA-approved drug used therapeutically against rheumatoid arthritis. Auranofin is 10 times more potent than Mtz, which makes it a promising therapy for amoebiasis [100]. The innate immune response by protein lactoferrin, an iron-chelating molecule that is responsible for avoiding pathogens to acquire iron in mucosae and infection sites, has been tested in ALA and IA [101,102]. Remarkably, bovine lactoferrin was able to cure ALA and synergize with Mtz in biological action. This observation is particularly important given that a reduced dose of Mtz can be used if combined with lactoferrin, with the same effect on the parasite, thus diminishing the side effects and toxicity of the drug. In addition, other properties of lactoferrin such as its anti-inflammatory activity can help resolve the amoebic abscesses [101].
Gold Complexes as Antitumor Agents
Astrid Sigel, Helmut Sigel in Metal Ions in Biological Systems, 2004
Following the discovery of the significant cytotoxic properties of selected gold(I) compounds, a series of investigations were carried out by the same group of researchers to identify the possible biomolecular targets of auranofin and its congeners. Already in 1985 an article by Mirabelli et al. appeared in Cancer Research reporting the evaluation of auranofin on 15 tumor models in mice [17]. It was observed that auranofin is active against P388 leukemia only when administered intraperitoneally; in contrast, the drug turned out to be completely inactive when administered intravenously, subcutaneously, or per os. Evaluation of the effects of auranofin in vitro demonstrated that cell cycle distribution was not appreciably modified; auranofin displayed no preferential cytotoxicity to cell populations either in logarithmic or plateau growth phase. Moreover, it was shown that auranofin inhibited DNA, RNA, and protein synthesis at cytotoxic concentrations but not in a selective manner. The cytotoxic activity and the cellular association of gold from auranofin were reported to be dose, time, and temperature dependent [18].
Anti-virulence strategies for Clostridioides difficile infection: advances and roadblocks
Published in Gut Microbes, 2020
David Stewart, Farhan Anwar, Gayatri Vedantam
Auranofin is an orally administered gold-containing compound; it is an anti-inflammatory compound that is used for treatment of rheumatoid arthritis. Recent studies have shown potential use of Auranofin as a broad-spectrum antimicrobial.84 Much like Ebselen, Auranofin has been shown to be efficacious in killing or limiting virulence in numerous, clinically notable pathogens. VRE was shown to be sensitive to Auranofin-insult, resulting in a significant decrease in bacterial titers in vitro. Sub-inhibitory concentrations inhibit biofilm formation while mature biofilms were eradicated in a dose-dependent manner.84 Furthermore, Auranofin protected mice against a lethal VRE challenge and decreased the titers of recoverable VRE from these mice.84,85 Similar results were seen with Auranofin treatment of multidrug-resistant staphylococci.86
Clostridioides difficile: innovations in target discovery and potential for therapeutic success
Published in Expert Opinion on Therapeutic Targets, 2021
Tanya M Monaghan, Anna M Seekatz, Benjamin H Mullish, Claudia C. E. R Moore-Gillon, Lisa F. Dawson, Ammar Ahmed, Dina Kao, Weng C Chan
Due to the critical and unmet need for developing new anti-CDI therapeutics, researchers have turned their attention to re-purposing drugs with well-studied safety and pharmacokinetic profiles. Auranofin (6; Figure 2) is a gold-containing anti-inflammatory FDA-approved anti-rheumatoid arthritis drug which possesses strong antibacterial and antifungal activities [125]. Similar to the anticlostridial antibiotic fidaxomicin, auranofin was observed to inhibit C. difficile growth, toxin production, and spore formation. Auranofin also produced a direct protective effect against C. difficile toxin-mediated inflammation in an in vitro assay, which was not observed with fidaxomicin [125,126]. Upon testing in a mouse model of CDI, auranofin significantly protected mice against CDI at low clinically achievable doses (0.125 mg/kg and 0.25 mg/kg) with 100% and 80% survival, respectively Auranofin is a promising candidate, with an unknown mechanism of action, which warrants further investigation as a novel treatment option for CDI.
Critical review of renal tubule karyomegaly in non-clinical safety evaluation studies and its significance for human risk assessment
Published in Critical Reviews in Toxicology, 2018
Another example of a therapeutic used in humans that was a consistent inducer of renal tubule karyomegaly in rats is auranofin. This drug has been marketed since 1985 when it was approved for treatment of rheumatoid arthritis. It is now being considered for repurposing with new therapeutic potential for many serious human diseases (Roder and Thompson 2015). The primary adverse effects of auranofin in humans concern gastrointestinal tract symptoms and skin irritations, but not commonly, renal conditions, a profile that contrasts directly with the karyomegalic kidney effects of auranofin in the rat. In the early development of auranofin, rheumatoid arthritis patients receiving either auranofin or sodium aurothiomalate did not show any clinical chemistry indications of nephrotoxicity after 6 months of treatment (Crisp et al. 1983). From the long history of clinical use, it can be inferred that renal tubule karyomegaly is not a human response to this compound. These examples suggest that the induction of renal tubule karyomegaly in laboratory animals is not generally predictive of similar kidney changes in humans.
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